Abstract

Obesity is a significant risk factor for colorectal cancer (CRC); however, the relative contribution of high-fat consumption and excess adiposity remains unclear. It is becoming apparent that obesity perturbs both the intestinal microbiome and gut metabolome, and each has the potential to induce pro-tumorigenic changes in the epithelial transcriptome. The physiologic consequences and the degree to which these different biologic systems interact remain poorly defined. To better understand the mechanisms by which obesity drives colonic tumorigenesis, we profiled the colonic epithelial transcriptome of high fat (HF) diet-induced and genetically-induced (DbDb) obese mice with a genetic predisposition to intestinal tumorigenesis (Apc1638N). 266 and 584 genes were differentially expressed in the colonic mucosa of HF and DbDb mice respectively. These genes mapped to pathways involved in immune function, and cellular proliferation and cancer. Furthermore, Akt was central within the networks of interacting genes identified in both gene sets. Co-expression analysis comparing associations between the colonic transcriptome and microbiome revealed that three bacterial taxa previously correlated with tumor burden were significantly correlated with a gene module enriched for Akt-related genes. Similarly, co-expression analysis of the colonic transcriptome and metabolome found that adenosine, which was negatively associated with inflammatory markers and tumor burden, was also correlated with a gene module enriched with Akt regulators. Our findings provide evidence that high-fat consumption and excess adiposity result in changes in the colonic transcriptome that, although distinct, both appear to converge on Akt signaling. Such changes could be mediated by alterations in the colonic microbiome and metabolome.